Many compositions are available for sedating patients or, in larger dosages, for inducing surgical anesthesia in patients. These materials are used alone or in combination with other agents, such as nitrous oxide, to induce narcosis and to raise the patients pain threshold so that the patient can withstand surgical procedures. Likewise in smaller doses, these materials can reduce anxiety and generally sedate the patient. For example the following compounds are in general use as sedative and anesthetic agents: thiopental sodium, 5-allyl-1-methyl-5-(1-methyl-2-pentynyl)barbituric acid sodium salt (brevitol), 2-bromo-2-chloro-1,1,1-trifloroethane (halothane), and the like.
Most anesthetic and sedative agents, in addition to their beneficial effects, also lower certain body functions, such as respiration, blood pressure and heart action. Lowered body functions may sometimes lead to complications, particularly in older patients and in patients suffering from cardiac and vascular diseases and diseases of the kidneys and liver. Likewise, reduction in blood pressure may also lead to circulatory insufficiency during the surgical procedures which, unless alleviated, may do serious harm even to patients who have previously exhibited no signs of heart, kidney or liver disfunction.
General anesthesia, administered as an inhaled or intravenous agent, for a surgical operation involves analgesia, amnesia, loss of consciousness, motionlessness and abolition of autonomic responses. The mechanism of action is still not completely understood, but most general anesthetics act at multiple molecular sites. The potential mechanisms of anesthesia action include protein receptor, lipid and ion channels. As the solubility of anesthetics increases in oil, so does the potency leading to the lipid theory developed by Meyer and Overton. There is also a correlation between anesthesia potency and the ability of the anesthetic to inhibit the enzyme activity of the protein, for example in firefly luciferase, a model used for studying anesthesia. In addition, potentiation of the inhibitory response, mediated by the neurotransmitter GABA (gamma-aminobutyric acid), dampens neuronal excitability placing the GABA receptor as a potential receptor site for anesthetic action. GABA is the major mediator of inhibitory synaptic transmission, and a family of ligand-gated chloride channel proteins. Other theories include NMDA and ligand-gated ion channels as a receptor. There is sufficient evidence supporting the blockade of Na+ channels and the activation of K+ channels.
The effects of anesthesia depend on the concentration at the site of action, although concentrations cannot be measured in the brain of humans, therefore the concentration in the blood or expired gas (for inhaled anesthetics) is evaluated. Current inhaled general anesthetics (including, halothane enflurane, nitrous oxide, desflurane, isoflurane and sevoflurane, shown below) have a low therapeutic index (usually 2-3), hence the discovery of a new structural class would help in the development of safer anesthetics.

The present invention is directed to derivatives of themisone, that have been found to have anticonvulsant and anesthetic activity. Themisone, also known as Atrolactamide, was found in the 1950's to be a very potent anticonvulsant. The racemic mixture protected 4 out of 4 mice against seizures at 250 mg/kg, however the compound was toxic (blood dyscrasias, rash). Applicants believe the toxicity of this compound results from the formation of 2-phenyl-acrylamide by an elimination reaction as shown below:
To prevent the formation of this potential metabolite in vivo, applicants have designed and synthesized derivatives of themisone that prevent the elimination and potential formation of 2-phenyl-acrylamide, a potential toxic metabolite. These compounds have been found to exhibit both anti-convulsant activity as well as anesthetic acitivity. Accordingly, one aspect of the present invention is directed to novel themisone derivatives that are blocked from forming 2-phenyl-acrylamide and the use of such compounds for reducing the incidence and severity of seizures and for use as a general anesthetic.